Bacterial Growth Laws: Origins and Consequences

It is a grand challenge of systems biology to make predictive connection between molecular level details and the physiology of an organism. In this talk, I will describe a top-down approach that reveals intrinsic mechanisms of growth-mediated global gene regulation in enteric bacteria, and predicts quantitatively how cell growth and gene expression affect one another. Building upon bacterial "growth laws" discovered by Maaloe et al 50 years ago and additional growth laws suggested by our own experiments, we developed a theory of bacterial growth, integrating salient elements of ribosome function, nutrient limitation, and metabolic control. The theory that emerged is very simple mathematically (consisting of three linear equations), but provides a comprehensive framework to understand the myriad of seemingly disparate data, with quantitative predictions validated by numerous experiments performed on a wide range of molecular systems in Escherichia coli. Among these is a quantitative description on the fitness cost of gratuitous gene expression, and the existence of various growth-mediated feedback routes that can significantly alter the behaviour of even simple, apparent open-loop genetic circuits. As the intrinsic growth-dependent effects described here can dominate over gene-specific regulatory effects, they should be taken into account in understanding the physiological response of endogenous circuits as well as in designing synthetic circuits capable of operating in a broad range of physiological conditions. Growth mediated feedback also suggests a very intriguing built-in mechanism for the rapid evolution of drug resistance.